The Farming and Movement Evaluation Study (FAME) is a case-control study of PD nested in the Agricultural Health Study, a cohort study of 89,000 licensed pesticide applicators and spouses designed to evaluate the role of farming-related exposures in chronic disease. The specific aims of FAME were to examine the relationship of PD to (i) pesticide exposure; (ii) other neurotoxicants, particularly metals; (iii) lifestyle factors including diet, smoking, and caffeine; (iv) skin melanin, to examine racial/ethnic differences; and (v) polymorphisms in genes involved in dopaminergic neurotransmission, xenobiotic metabolism, or xenobiotic-specific membrane transport. We enrolled 115 cases and 384 controls. PD diagnosis was verified by movement disorder specialists. Controls were a random sample from the remaining cohort, frequency matched to cases by age, sex, and state. Exposure was evaluated using data from three complementary sources: (i) interview information on pesticide use, other exposures, and lifestyle already collected in the AHS; (ii) blood samples to measure organochlorines and metals and for DNA banking; and (iii) new telephone interviews which obtained information on specific pesticides implicated in PD as well as other neurotoxicants. Pesticides and PD: Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of PD. Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Using FAME data, we found that PD was associated with use of a group of pesticides that inhibit mitochondrial complex I (OR 1.7, 95% CI, 1.02.8), including rotenone (OR 2.5, 95% CI, 1.34.7), and with use of a group of pesticides that cause oxidative stress (OR 2.0, 95% CI, 1.23.6), including paraquat (OR 2.5; 95% CI, 1.44.7). This is the first study to show an association of PD with rotenone, a known mitochondrial toxicant used in one of the most robust animal models of PD. The study also extends previous work on PD and paraquat with more detailed data, showing for example a dose-response. Our finding that PD was positively associated with two groups of pesticides defined by mechanisms previously implicated experimentally supports a role for these mechanisms in PD pathophysiology. Paraquat, glutathione transferases, and PD: Paraquat is one of the most widely used herbicides worldwide. It produces a PD model in rodents through redox cycling and oxidative stress and is associated with PD risk in humans. Glutathione transferases provide cellular protection against oxidative stress and could potentially modulate paraquat toxicity. We investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione-S-transferase M1 (GSTM1) or T1 (GSTT1). There was no interaction of paraquat with GSTM1. In contrast, GSTT1 genotype significantly modified the association of paraquat with PD (p-interaction=0.027). In men with functional GSTT1, the OR for paraquat was 1.5 (95% CI 0.63.6), while in men with homozygous GSTT1 deletion, the OR was 11.1 (95% CI 3.044.6). Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. The GSTT1 deletion is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat. Dietary fat, pesticide exposure, and PD: Dietary fat intake may modify PD risk directly or by altering the response to environmental neurotoxicants including pesticides. Using data from FAME, we evaluated diet and pesticide use 10 years before diagnosis in 89 cases or a corresponding date in 336 frequency-matched controls. PD was inversely associated with N-3 polyunsaturated fatty acids (PUFAs) (OR 0.4, 95% CI 0.2-0.8 for highest vs lowest tertile) and the N-3 precursor &#61537;-linolenic acid (0.4, 0.2-0.8). Moreover, associations of PD with paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 (1.5-12) in individuals with PUFA intake below the median but 1.2 (0.4-3.4) in those with higher intake (p-interaction=0.10). The OR for rotenone was 5.8 (2.3-15) in those with saturated fat intake above the median but 1.5 (0.5-4.2) in those with lower intake (p-interaction=0.02). Thus, high PUFA intake, which may mitigate neuroinflammation, moderated the PD risk associated with paraquat. In contrast, high saturated fat intake, which may increase oxidative stress, increased PD risk associated with rotenone. alpha-synuclein, head injury, and PD: Sporadic PD is associated with both head injury and SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding alpha-synuclein. We evaluated the hypothesis that SNCA Rep1 modifies the association between head injury and PD risk in sporadic cases. Data from FAME were combined with data from a second case-control study of PD, the Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH). Consistent with prior reports, short Rep1 genotype was associated with reduced PD risk and long Rep1 with increased risk, relative to medium-length Rep1. Head injury was not significantly associated with PD overall (OR 1.3, 95% CI 0.91.8), nor among those with short or medium-length Rep1. However, head injury was strongly associated with PD in those with long Rep1 (OR 3.5, 95% CI 1.49.2, p-interaction=0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p=0.03). While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of alpha-synuclein are high, as in those with Rep1 expansion.